Abstract POSTER-THER-1421: Epigenetic targeting of ovarian cancer stem cells

Abstract

Abstract In ovarian and other cancers, emerging data indicate that cancer stem cells contribute to chemoresistance and that their persistence alters clinical outcome. As epigenetic regulators play a major role in the control of normal stem cell differentiation, epigenetics may play a critical role in targeting this subpopulation. Epigenetic aberrations, especially DNA methylation, result in silencing of tumor suppressor and differentiation-associated genes and regulate ovarian cancer stem cell (OCSCs) survival. To test the hypothesis that DNA hypomethylating agents “reset” OCSCs towards differentiation, we investigated the effect of the new DNA methytransferase inhibitor SGI-110 on OCSCs, defined as aldehyde dehydrogenase 1 (ALDH)(+) cells. We demonstrated that ALDH(+) OC cells possess multiple stem cell characteristics, were highly chemoresistant, and were enriched in xenografts residual after platinum therapy. Low dose SGI-110 reduced the stemness properties of ALDH(+) cells, including their tumor initiating capacity, resensitized these OCSCs to platinum, and induced re-expression of differentiation-associated genes. Maintenance treatment with SGI-110 after carboplatin inhibited OCSCs, caused profound global tumor hypomethylation, and delayed tumor progression, supporting epigenomic targeting as a novel strategy after platinum-based therapy in OC. Collectively, our data suggest that a strategy targeting DNA methylation in OC exerts potent anti-tumor activity by allowing elimination of OCSCs enriched in residual, platinum resistant tumors. Our study provides the first evidence that epigenome targeting strategies delay tumor progression by targeting and reprogramming residual cancer stem cells, suggesting that SGI-110 in combination with platinum has the potential to prevent recurrent and chemoresistant OC. Citation Format: Yinu Wang, Horacio Cardenas, Fang Fang, Salvatore Condello, Pietro Taverna, Matthew Segar, Yunlong Liu, Daniela Matei, Kenneth P. Nephew. Epigenetic targeting of ovarian cancer stem cells [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1421.